African children diagnosed with HIV infection late in disease have a mortality rate often exceeding 20%, and there is an urgent need for novel strategies to improve their prognosis. Epstein-Barr virus (EBV) viremia is commonly detected in critically ill HIV-infected children, with unknown relevance. Sub-clinical malaria parasitemia is also common in many regions of the HIV epidemic, and is immunomodulatory, interacting with both HIV and EBV. The project will study EBV viremia and malaria parasitemia in a cohort of children with late HIV diagnosis in hospital. The study will determine the prevalence correlates, and clinical relevance of EBV viremia (Aim 1) and malaria parasitemia (Aim 2), and their combined effect on immune recovery during initiation of antiretroviral therapy (Aim 3). It is hypothesized that EBV viremia and malaria will each affect ~50% of children, and will be associated with mortality, impaired immune restoration, and higher B cell and T cell activation after 6 months of antiretroviral therapy. Results may inform the development of novel interventions for this population. The study will be conducted using archived specimens and data from a cohort of 181 hospitalized Kenyan children enrolled in the Pediatric Urgent Start of HAART (PUSH) Study. Children were diagnosed with HIV at admission, started on antiretroviral therapy (ART), and followed longitudinally with serial plasma and PBMC specimens stored over 24 weeks. We will use quantitative PCR to assess EBV DNA levels and determine the prevalence and duration of EBV viremia. Ultrasensitive q-RT-PCR will be used to measure malaria parasite levels in blood. Flow cytometry will be used to describe activated and memory T and B cell populations. Regression models will be used to define correlates and clinical consequences of EBV viremia, and malaria parasitemia and immunologic recovery. By defining the relationships between EBV viremia, malaria parasitemia, and clinical and immunologic outcomes among severely ill HIV-infected children, the study will inform interventions to reduce the high mortality rate in this population.